This project is directed, in the broadest sense, toward the understanding of the chemical architecture of the brain and particularly the macromolecular complexes of the myelin sheath. During the proposed period the chemistry of proteolipids from brain subcortical white matter will be studied. Proteolipids are lipoproteins which are soluble in chloroform-methanol and insoluble in water. An apoprotein can be obtained free of complex lipids in a form soluble in chloroform- methanol but which can be converted to a water soluble form. The program is specifically directed toward the determination of the complete amino acid sequence of the "classical" white matter proteolipid of Folch and Lees with the purpose of characterizing the nature of the sequences which give rise to the unusual solubility of the protein. Although physical heterogeneity of the preparatigns is apparent, convincing evidence for chemical heterogeneity is lacking. Techniques to be used provide the basis for a rational approach to the separation of different proteins, if such should be demonstrated. The program requires the preparation of chemically modified proteolipids, the controlled enzymatic and chemical cleavage of the protein and the separation and purification of sufficient amounts of peptides for sequencing. In the course of these studies information on the chemical properties and possible subunit structure of the proteolipid will be obtained. The position of the covalently bound fatty acid residues in the apoprotein will be located. Comparable sequence studies will be carried out on proteolipids from other animal species and other brain regions. The procedures will also provide peptides and chemically modified proteins for studies of the encephalitogenic and antigenic properties of the proteolipid apoprotein. The observation that proteolipids can be cleaved in vitro by proteolytic enzymes suggests that a comparable breakdown might occur in vivo. These investigations are applicable to an understanding of multiple sclerosis and could potentially provide either a new animal model or a diagnostic test for susceptibility to MS.